PROJECT SUMMARY The goal of this exploratory proposal is to evaluate the feasibility and potential efficacy of lamotrigine (LTG), a voltage-gated sodium channel inhibitor that blunts glutamatergic transmission, for treating adolescents with alcohol use disorder (AUD). Alcohol use typically begins during adolescence and prevalence rates for AUD peak before age 21. Yet, despite clinical demand, treatments for youth rely on psychosocial interventions that yield only modest benefits; most return to hazardous drinking. One potential way to improve adolescent alcohol treatment is to augment the best available psychosocial interventions with pharmacotherapy. Although the FDA approved four medications to treat AUD in adults, no medication is indicated for adolescents, and controlled clinical trials with teenagers are almost nonexistent. Optimizing treatment options for youth will require closing this gap in medication development research. Prior work shows that anticonvulsants attenuate alcohol withdrawal, blunt craving, and reduce alcohol and other drug use. While these medications yield medium additive effects on drinking outcomes when paired with psychosocial treatments, they are poorly tolerated, especially by youth, which undermines their clinical utility. We propose to explore LTG, an anticonvulsant with a minimal side effect profile that is well-tolerated and shown to reduce alcohol and other drug use in adults. Its effects on adolescent AUD, however, are untested. This proof-of-concept study will leverage an innovative approach to medication development for youth with AUD that pairs human laboratory and ecological momentary assessment (EMA) methods. Adolescents with alcohol use disorder (N = 50, ages 16-19 years) will be randomized to LTG or placebo. A 6-week titration period will be followed by 3 weeks at the target dose (200 mg/day) and a two-week taper period. As in our prior work, all youth will receive a five session behavioral platform comprised of motivational enhancement therapy and alcohol-focused cognitive behavioral therapy. This behavioral platform affords the most meaningful and ethical test of LTG in this vulnerable and high-risk population. A 3-month follow-up will evaluate sustained benefit. Our major aims are to evaluate the feasibility and tolerability of LTG among adolescents with AUD, apply our human laboratory and EMA paradigms to evaluate the effects of LTG on intermediate phenotypes associated with alcohol use and outcomes in clinical trials, and evaluate the effects of LTG on alcohol use at the target dose and at the 3-month follow-up. This study is intended to fill a critical void in medication development for adolescents with AUD. Our aims also address national priorities to gather safety and efficacy data on medications for treating AUD in youth. Results from this proof-of-concept study will inform whether a larger (R01) clinical trial is warranted.